Delayed wound healing in CXCR2 knockout mice.

Previous studies demonstrated that the CXC chemokine, MGSA/GRO-alpha and its receptor, CXCR2, are expressed during wound healing by keratinocytes and endothelial cells at areas where epithelialization and neovascularization occur. The process of wound healing is dependent on leukocyte recruitment, keratinocyte proliferation and migration, and angiogenesis. These processes may be mediated in part by CXC chemokines, such as interleukin-8 and MGSA/GRO-alpha. To examine further the significance of CXC chemokines in wound healing, full excisional wounds were created on CXCR2 wild-type (+/+), heterozygous (+/-), or knockout (-/-) mice. Wounds were histologically analyzed for neutrophil and monocyte infiltration, neovascularization and epithelialization at days 3, 5, 7, and 10 postwounding. The CXCR2 -/- mice exhibited defective neutrophil recruitment, an altered temporal pattern of monocyte recruitment, and altered secretion of interleukin-1beta. Significant delays in wound healing parameters, including epithelialization and decreased neovascularization, were also observed in CXCR2 -/- mice. In vitro wounding experiments with cultures of keratinocytes established from -/- and +/+ mice revealed a retardation in wound closure in CXCR2 -/- keratinocytes, suggesting a role for this receptor on keratinocytes in epithelial resurfacing that is independent of neutrophil recruitment. These in vitro and in vivo studies further establish a pathophysiologic role for CXCR2 during cutaneous wound repair.

[1]  M. Burdick,et al.  The CXC Chemokine Receptor 2, CXCR2, Is the Putative Receptor for ELR+ CXC Chemokine-Induced Angiogenic Activity1 , 2000, The Journal of Immunology.

[2]  M. Suematsu,et al.  Chronic inflammation upregulates chemokine receptors and induces neutrophil migration to monocyte chemoattractant protein-1. , 1999, The Journal of clinical investigation.

[3]  A. Richmond,et al.  Multiple chemotactic factors: fine control or redundancy? , 1999, Trends in pharmacological sciences.

[4]  E. Bröcker,et al.  Chemokines IL-8, GROalpha, MCP-1, IP-10, and Mig are sequentially and differentially expressed during phase-specific infiltration of leukocyte subsets in human wound healing. , 1998, The American journal of pathology.

[5]  T. Ley,et al.  Augmented inflammatory responses and altered wound healing in cathepsin G-deficient mice. , 1998, Archives of surgery.

[6]  T. Tumpey,et al.  Role of MIP-2 in neutrophil migration and tissue injury in the herpes simplex virus-1-infected cornea. , 1998, Investigative ophthalmology & visual science.

[7]  R. Terkeltaub,et al.  The murine homolog of the interleukin-8 receptor CXCR-2 is essential for the occurrence of neutrophilic inflammation in the air pouch model of acute urate crystal-induced gouty synovitis. , 1998, Arthritis and rheumatism.

[8]  R. Cardiff,et al.  Delayed wound healing and disorganized neovascularization in transgenic mice expressing the IP-10 chemokine. , 1998, Proceedings of the Association of American Physicians.

[9]  M. Burdick,et al.  MIP-1alpha as a critical macrophage chemoattractant in murine wound repair. , 1998, The Journal of clinical investigation.

[10]  M. Sticherling,et al.  The CXC receptor 2 is overexpressed in psoriatic epidermis. , 1998, The Journal of investigative dermatology.

[11]  S. McColl,et al.  Chemokine networks in vivo: involvement of C-X-C and C-C chemokines in neutrophil extravasation in vivo in response to TNF-alpha. , 1997, Journal of immunology.

[12]  M. Burdick,et al.  Chemokine and inflammatory cytokine changes during chronic wound healing , 1997, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[13]  D. Heimbach,et al.  Monocyte chemoattractant protein-1 mRNA expression in the human burn wound. , 1997, The Journal of surgical research.

[14]  Paul Martin,et al.  Wound Healing--Aiming for Perfect Skin Regeneration , 1997, Science.

[15]  J. Hansbrough,et al.  Role of Melanoma growth stimulatory activity (MGSA/gro) on keratinocyte function in wound healing , 1997, Archives of Dermatological Research.

[16]  S. Werner,et al.  Differential regulation of pro-inflammatory cytokines during wound healing in normal and glucocorticoid-treated mice. , 1996, Cytokine.

[17]  S. Werner,et al.  Transforming Growth Factors 1, 2, and 3 and Their Receptors Are Differentially Regulated during Normal and Impaired Wound Healing (*) , 1996, The Journal of Biological Chemistry.

[18]  I. Becker,et al.  Differential expression of chemokines in patients with localized and diffuse cutaneous American leishmaniasis. , 1996, The Journal of infectious diseases.

[19]  T. Mitchison,et al.  Actin-Based Cell Motility and Cell Locomotion , 1996, Cell.

[20]  L. Nanney,et al.  Cell biology of wound healing. , 1996, International review of cytology.

[21]  H. Larjava,et al.  Keratinocytes in Human Wounds Express αvβ6 Integrin , 1996 .

[22]  A. Richmond,et al.  Distributions of melanoma growth stimulatory activity of growth-regulated gene and the interleukin-8 receptor B in human wound repair. , 1995, The American journal of pathology.

[23]  S. Werner,et al.  Suppression of keratinocyte growth factor expression by glucocorticoids in vitro and during wound healing. , 1995, The Journal of investigative dermatology.

[24]  M. Ackermann,et al.  Neutrophilia in mice that lack the murine IL-8 receptor homolog. , 1995, Science.

[25]  W. Wood,et al.  Chemokine binding and activities mediated by the mouse IL-8 receptor. , 1995, Journal of immunology.

[26]  K. Aldape,et al.  Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling. , 1995, Journal of cell science.

[27]  L. Nanney,et al.  Assessment of differential cytokine effects on angiogenesis using an in vivo model of cutaneous wound repair. , 1995, The Journal of surgical research.

[28]  E. Fuchs,et al.  Gene targeting of BPAG1: Abnormalities in mechanical strength and cell migration in stratified epithelia and neurologic degeneration , 1995, Cell.

[29]  D. Foreman,et al.  Neutralisation of TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring. , 1995, Journal of cell science.

[30]  B. Dewald,et al.  Actions of the chemotactic cytokines MCP‐1, MCP‐2, MCP‐3, RANTES, MIP‐1α and MIP‐1β on human monocytes , 1995 .

[31]  J. Paulauskis,et al.  Functional characterization of the rat chemokine KC and its importance in neutrophil recruitment in a rat model of pulmonary inflammation. , 1995, Journal of immunology.

[32]  L. Nanney,et al.  Immunolocalization of collagenase and TIMP in healing human burn wounds. , 1994, The Journal of investigative dermatology.

[33]  W. Wood,et al.  Neutrophil and B cell expansion in mice that lack the murine IL-8 receptor homolog. , 1994, Science.

[34]  T. Kensler,et al.  Myeloperoxidase as a biomarker of skin irritation and inflammation. , 1994, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[35]  S. L. Gonias,et al.  Classification of alpha 2-macroglobulin-cytokine interactions based on affinity of noncovalent association in solution under apparent equilibrium conditions. , 1994, The Journal of biological chemistry.

[36]  L. Nanney,et al.  Localization of mRNAs representing collagenase and TIMP in sections of healing human burn wounds. , 1993, The American journal of pathology.

[37]  A. Giannetti,et al.  Distinctive integrin expression in the newly forming epidermis during wound healing in humans. , 1993, The Journal of investigative dermatology.

[38]  M. Klagsbrun,et al.  Appearance of heparin-binding EGF-like growth factor in wound fluid as a response to injury. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[39]  D. Taub,et al.  Preferential migration of activated CD4+ and CD8+ T cells in response to MIP-1 alpha and MIP-1 beta , 1993, Science.

[40]  H. Dvorak,et al.  Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing , 1992, The Journal of experimental medicine.

[41]  R. Maisel,et al.  Angiogenic Growth Factors: Their Effects and Potential in Soft Tissue Wound Healing , 1992, The Annals of otology, rhinology, and laryngology.

[42]  M. Baggiolini,et al.  Differential effects of neutrophil-activating peptide 1/IL-8 and its homologues on leukocyte adhesion and phagocytosis. , 1991, Journal of immunology.

[43]  D. Goeddel,et al.  Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES , 1990, Nature.

[44]  L. Nanney.  Epidermal and dermal effects of epidermal growth factor during wound repair. , 1990, The Journal of investigative dermatology.

[45]  E. Appella,et al.  Human monocyte chemoattractant protein‐1 (MCP‐1) Full‐length cDNA cloning, expression in mitogen‐stimulated blood mononuclear leukocytes, and sequence similarity to mouse competence gene JE , 1989, FEBS letters.

[46]  M J Banda,et al.  Wound macrophages express TGF-alpha and other growth factors in vivo: analysis by mRNA phenotyping. , 1988, Science.

[47]  S. Yuspa,et al.  Dimethyl sulfoxide-induced enhancement of 7,12-dimethylbenz(a)anthracene metabolism and DNA binding in differentiating mouse epidermal cell cultures. , 1976, Cancer research.

[48]  R. Ross,et al.  The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. , 1975, The American journal of pathology.